Stereoselective disposition of ibuprofen enantiomers in man.

This study has examined the stereoselective disposition of the enantiomers of ibuprofen in four healthy male subjects following separate administration of racemic ibuprofen (800 mg) and of each enantiomer (400 mg). A mean of 63 +/- 6% of an administered dose of R(-) ibuprofen was stereospecifically inverted to the S(+) enantiomer. There were no measurable inversion of the S(+) to R(-) ibuprofen. The kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode. It is likely that this change reflects an interaction between the enantiomers at plasma protein binding sites. It was found that formation of ester glucuronide conjugates stereoselectively favoured the S(+) enantiomer. The data have demonstrated that the pharmacokinetics of ibuprofen and other alpha-methylarylacetic acids cannot be interpreted adequately without studying the pharmacokinetics of the individual enantiomers.     

Stereoselective disposition of talinolol in man

The disposition of the beta-blocking drug talinolol is controlled by P-glycoprotein in man. Because talinolol is marketed as a racemate, we reevaluated the serum-concentration time profiles of talinolol of a previously published study with single intravenous (30 mg) and repeated oral talinolol (100 mg for 14 days) before and after comedication of rifampicin (600 mg per day for 9 days) in eight male healthy volunteers (age 22-26 years, body weight 67-84 kg) with respect to differences in the kinetic profiles of the two enantiomers S(-) talinolol and R(+) talinolol. Additionally, the metabolism of talinolol in human liver microsomes was examined. After oral administration, S(-) talinolol was slightly less absorbed and faster eliminated than R(+) talinolol. The absolute bioavailabilty of the R(+) enantiomer of talinolol was slightly but significantly higher than of its S(-) enantiomer. Coadministration of rifampicin further intensified this difference in the disposition of R(+) and S(-) talinolol (p < 0.05). Formation of 4-trans hydroxytalinolol was the major metabolic pathway in human liver microsomes. All Cl(int) values of S(-) were higher than of R(+) talinolol; 0.1 microM ketoconazole inhibited the formation of all metabolites. In conclusion, the stereoselectivity of talinolol disposition is of minor importance, and most likely caused by presystemic biotransformation via CYP3A4. The less active R(+) talinolol might be suitable for phenotyping P-glycoprotein expression in man.     

Effects of ciprofloxacin on the stereoselective disposition of mexiletine in man

Mexiletine is extensively metabolized in man, with less than 10% of the dose being excreted unchanged in urine. Clinical drug-drug interaction studies as well as in vitro drug metabolism studies suggest that CYP1A2, in addition to CYP2D6, is involved in the metabolism of mexiletine in man. Therefore, the objective of the study was to determine whether potential inhibition of CYP1A2 by the quinolone antibiotic agent ciprofloxacin would alter the stereoselective disposition of mexiletine. Nineteen healthy men (10 smokers and 9 nonsmokers) received a single 200-mg oral dose of racemic mexiletine hydrochloride on 2 occasions: once alone and once during concomitant administration of ciprofloxacin 750 mg BID (starting 3 days before and up to 2 days after the administration of mexiletine). Serial blood and urine samples were collected for 48 hours, and pharmacokinetic parameters were derived. Total clearances of R-(-)- and S-(+)-mexiletine were 42% and 63% higher in smokers compared with nonsmokers (P < 0.05). This observation is in agreement with increased clearance of mexiletine under conditions of increased CYP1A2 activity. On the other hand, ciprofloxacin administration only marginally decreased R-(-)- and S-(+)-mexiletine clearances (2 to 5 L/h; P < 0.05) secondary to a decrease in mexiletine nonrenal clearance. In conclusion, the increase in mexiletine nonrenal clearance in smokers and its decrease during the combined administration of ciprofloxacin confirm the role of CYP1A2 in the overall clearance of the drug. Nevertheless, results obtained in this study suggest that no major drug interaction is to be expected during the concomitant administration of ciprofloxacin and mexiletine in patients.     

Stereoselective disposition of the antiarrhythmic agent mexiletine during the concomitant administration of caffeine

Caffeine consumption is extensive in industrialized countries and its role in drug-drug interactions is often overlooked. CYP1A2, the major cytochrome P450 isoform involved in the metabolism of caffeine, has also been implicated in the formation of N-hydroxymexiletine, the major metabolite of mexiletine. Therefore, the objective of this study was to assess the effects of a clinically relevant dosage of caffeine on the stereoselective disposition of mexiletine. Fourteen healthy volunteers--10 extensive metabolizers (EMs) and 4 poor metabolizers (PMs) of CYP2D6--received a single 200 mg oral dose of racemic mexiletine hydrochloride on two occasions (1 week apart): once by itself and once during administration of caffeine (100 mg four times daily). Serial blood and urine samples were collected and pharmacokinetic parameters were estimated. Although the total clearance of mexiletine was not significantly altered by the coadministration of caffeine in EMs and PMs, a stereoselective decrease (16% in EMs and 14% in PMs) in the urinary recovery of N-hydroxymexiletine from the R-(-)-enantiomer was observed. Also, the partial metabolic clearance of R-(-)-mexiletine to N-hydroxymexiletine glucuronide was reduced from 126 +/- 48 mL/min to 106 +/- 32 mL/min and 152.6 (73.4-196.2) mL/min to 109 (77-127) mL/min by the coadministration of caffeine in EMs and PMs, respectively. Consequently, the R/S ratio for urinary recovery and the partial metabolic clearance of mexiletine to N-hydroxymexiletine were 28% lower during the coadministration of caffeine. In conclusion, data obtained in this study indicate that coadministration of caffeine does not lead to clinically significant changes in mexiletine plasma concentrations. However, results obtained suggest that CYP1A2 is involved in the formation of N-hydroxymexiletine.     

Stereoselective analysis of the disposition of tosufloxacin enantiomers in man

Summary The pharmacokinetics of tosufloxacin enantiomers after oral administration of racemic tosufloxacin were examined in healthy volunteers. Only small differences were observed in time to peak concentration (2.6±0.3 [mean ± SEM] h for (+)-tosufloxacin vs 2.4±0.2 h for (–)-tosufloxacin), elimination half-life (3.61±0.24 h vs 3.49±0.23 h), and area under the curve (2.78±0.19 h·g/ml vs 2.87±0.19 h·g/ml); however, peak concentration (0.40±0.03 g/ml vs 0.44±0.03 g/ml), renal clearance (226±10 ml/min vs 202±10 ml/min), and urinary recovery (35.4±2.2% vs 32.4±1.9%) differed significantly between enantiomers.     

Stereoselective disposition of flurbiprofen in normal volunteers.

1. The concentrations of the R- and S-enantiomers of flurbiprofen and its metabolites were measured in plasma and urine following the oral administration of 50 mg racemic flurbiprofen to six normal volunteers. 2. The AUC and half-life of the R-enantiomer were significantly lower than the corresponding S-enantiomer values reflecting the greater clearance of R-flurbiprofen (20.42 +/- 4.71 vs 16.12 +/- 3.60 ml min-1). 3. Ex vivo protein binding studies indicated that the percent unbound of R-flurbiprofen was (not significantly) greater than that of the S-enantiomer (0.055 +/- 0.008 vs 0.049 +/- 0.009) and the corresponding unbound clearances did not show enantioselectivity. 4. Both enantiomers were cleared primarily by metabolism to an acylglucuronide and 4'-hydroxyflurbiprofen. There was significant enantioselectivity (R greater than S) in the formation clearances of these metabolites which remained when unbound metabolite formation clearances were considered. 5. In conclusion, the disposition of the enantiomers of flurbiprofen exhibits enantioselectivity at the level of protein binding and metabolite formation.     

Stereoselective disposition of indoprofen in surgical patients.

The pharmacokinetics of the enantiomers of indoprofen were determined after intravenous administration of the racemate to 10 surgical patients. The mean volume of distribution was 8.97 +/- 2.21 (s.d.) 1 for the pharmacologically active S(+)-enantiomer and 12.60 +/- 4.21 1 for the R(-)-enantiomer (P less than 0.001). The corresponding values for clearance were 32.2 +/- 11.1 ml min-1 and 48.8 +/- 15.5 ml min-1 (P less than 0.001). There was no significant difference in mean terminal half-life between the enantiomers.     

Stereoselective disposition of flurbiprofen in uraemic patients.

1. Both single and multiple oral doses of 50 mg racemic flurbiprofen were given to eight patients with mild to moderate renal impairment. The plasma and urine concentrations of the R- and S-enantiomers of flurbiprofen and its major metabolites were measured by a stereoselective h.p.l.c. assay. 2. For R-flurbiprofen the oral clearance (mean +/- s.d.: 38.3 +/- 12.8 vs 30.8 +/- 11.5 ml min-1) and volume of distribution (Vz; 17.6 +/- 3.9 vs 14.6 +/- 2.5 l) were significantly greater (P less than 0.05) than for the S-enantiomer. A significantly greater (P less than 0.05) percent of the dose was excreted in the urine R-configuration (16.4 +/- 6.0 vs 10.9 +/- 4.2%). 3. Plasma protein binding of the enantiomers of flurbiprofen was determined by ultrafiltration. The unbound clearance and unbound Vz were not different between enantiomers consistent with the (not significantly) greater percent unbound of R-flurbiprofen (0.079 +/- 0.014%) vs S-flurbiprofen (0.064 +/- 0.015%). 4. Relative to normal volunteers, the uraemic subjects exhibited a significantly greater (P less than 0.05) oral clearance, Vz and percent unbound for both enantiomers; unbound clearance and unbound Vz did not differ from healthy controls. 5. The disposition of flurbiprofen enantiomers was not changed upon multiple dosing and no evidence of futile cycling was found. Adjustment of flurbiprofen dosing rate in uraemic subjects is not indicated on the basis of pharmacokinetics.     

Stereoselective disposition of etodolac enantiomers in synovial fluid.

The synovial fluid (SF) uptake of the chiral nonsteroidal anti-inflammatory drug, etodolac, was studied in six arthritic patients, 2 hours (n = 1) or 12 hours (n = 5) after a single 200 mg dose of racemate. Marked stereoselectivity was seen in both SF and plasma; concentrations of pharmacologically inactive R-etodolac were up to 10-fold greater than active S-etodolac. Concentrations of S-etodolac were greater in SF than in plasma (SF:plasma ratio = 1.98 +/- 0.8): No such difference was seen for R-etodolac (SF:plasma = 0.91 +/- 0.3). Considerable concentrations of conjugated enantiomers were present in SF. In vitro equilibrium dialysis studies in drug-spiked samples showed that the unbound fraction of both enantiomers in SF was greater than in plasma; both fluids bound R more extensively than S etodolac. Therapeutically active S-etodolac has greater concentrations in synovial fluid than plasma during the post-distributive phase, which may be of possible clinical relevance.     

Stereoselective drug disposition: potential for misinterpretation of drug disposition data.

1. Although it is well recognised that the enantiomers of a chiral drug may possess different pharmacokinetic and pharmacodynamic properties, many studies dealing with chiral drugs which are administered as their racemates rely on non-stereoselective analytical techniques. 2. We present a theoretical analysis to illustrate the potential which exists for misinterpretation of drug disposition and plasma drug concentration-effect data generated for a racemic drug using a non-stereoselective assay. 3. It was shown that the use of such an analytical method can lead to the collection of data which may be both quantitatively and qualitatively inaccurate with respect to the individual enantiomers. For example, the clearance of the unresolved drug may indicate concentration- and time-dependence even though this pharmacokinetic process is concentration- and time-independent for each of the enantiomers. 4. The problems discussed emphasise the need to consider stereoselectivity in clinical pharmacological studies involving racemic drugs.     

Stereoselective disposition of carvedilol in man after intravenous and oral administration of the racemic compound

The racemic compound carvedilol is a multiple-action oral antihypertensive drug that exhibits both vasodilator and non-selective beta-adrenergic blocking activities. The effects of the levorotatoryS-enantiomer [S( – )-CARV] are vasodilatation and beta-blockade. TheR (+)-enantiomer [R (+)-CARV] is a pure vasodilating agent. Quantitative determination of the enantiomers in human plasma by HPLC was carried out after formation of diastereoisomers with the chiral reagent 2,3,4,6-tetraO-acetyl--d-glucopyranosyl isothiocyanate (GITC). The pharmacokinetics of the enantiomers were studied following i. v. (12.5 mg in 1 h) and p. o. (50 mg) administration of racemic carvedilol in ten healthy male subjects according to a randomized crossover design. The AUCs ofS (–)-CARV were significantly lower than those ofR (+)-CARV after both i. v. and p. o. administration. The systemic clearance of the two enantiomers was significantly different, whereas half-lives and apparent distribution volumes were comparable. Following p. o. administration, the absolute bioavailability (31.1% and 15.1%, respectively) and maximal plasma concentrations ofR (+ )-CARV were twice those ofS (–)-CARV A similar difference was found in the half-lives. A close correlation existed between enantiomeric ratios after i.v. and after p. o. administration, demonstrating slight intraindividual variability. The preferential systemic clearance of theS ( – )-enantiomer suggests stereoselective hepatic metabolism of carvedilol, becoming especially apparent after p. o. administration. The small intrasubject variability in enantiomer ratios indicates a relatively constant relation of beta-blockade to vasodilation during chronic treatment.     

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Since both (R)- and (S)-enantiomers of ibuprofen may act on the central nervous system, we investigated their plasma and cerebrospinal fluid (CSF) concentrations in 46 patients with nerve-root compression pain requiring a lumbar puncture. Each patient received an oral dose of 800 mg rac-ibuprofen. A single blood and CSF sample was drawn concomitantly from each patient at intervals between 30 min and 8 h after dosing. Both isomers peaked later in the CSF (3 h) than in the plasma (1.5 h). Their CSF concentrations became higher than their concurrent free plasma concentrations after 90 min. The estimated elimination half-lives of (R)- and (S)-ibuprofen were 1.7 h and 2.5 h in plasma and 3.9 h and 7.9 h in CSF, respectively. The AUCCSF/AUCplasma ratios (0, 8 h) were 0.009 and 0.015 for the (R)- and (S)-forms, respectively.     

Stereoselective disposition of hydratropic acid in rat

The stereoselective distribution, metabolism, and excretion of 2-phenylpropionic acid (hydratropic acid, HTA) was studied by giving racemic HTA (20 mg/kg) to intact, bile duct-cannulated, bile duct-ligated, and nephrectomized and bile duct-cannulated rats. In intact rats, the percentage of (R)-(-)-HTA in plasma was 53%, but 46-48% in various tissues at 5 min after dosing. A slightly higher binding affinity of (R)-(-)-HTA to plasma protein than the (S)-(+) form should be one of the important factors controlling the enrichment of (S)-(+)-HTA percentage in tissues and the increase of (R)-(-)-HTA percentage in plasma shortly after administration of racemate. About 66% of the dose was excreted in urine of intact rats (HTA acyl glucuronide (HTA-G): 54%; HTA: 12%) in 8 hr. Bile duct-cannulated rats excreted about 51% of the dose in bile as HTA-G and 40% in urine (HTA-G: 32%; HTA: 8%) in 6 hr. The (R)-(-)-enantiomer percentage of biliary HTA-G was about 25%, urinary HTA-G was 45%, and HTA was 57%. Since about 63% of the dose was excreted in bile and urine as the (S)-(+)-enantiomer after injection of racemate to bile duct-cannulated rats, stereoselective isomerization of (R)-(-)-HTA to the (S)-(+) form is suggested. The (R)-(-)-enantiomer percentage of HTA-G in urine decreased with ligation of the bile duct, but that of the HTA-G in 0-30-min bile was not influenced by nephrectomy. These results suggest that the step regulating stereoselective excretion of HTA-G in rats is that of its excretion from the liver into bile and blood. There should be no or very little stereoselectivity in the step of HTA-G excretion through the kidney into the urine.     

Stereoselective disposition of ibuprofen enantiomers in infants

The pharmacokinetics of the enantiomers of ibuprofen were investigated after oral administration of a single 7.6 ± 0.3 mg kg^-1 dose of the racemate in 11 infants. Mean (± s.d.) half-lives were 1.6 ± 0.5 h for S(+) and 1.5 ± 0.5 h for R(-) and mean (± s.d.) AUC values were 31.5 ± 14.3 mg l^-1 h for S(+) and 36.6 ± 13.8 mg l^-1 h for R(-). Since plasma concentrations of the active S(+)-isomer were lower than those reported in adults, a higher dosage might be required in infants.     

Stereoselective ring oxidation of propranolol in man.

The objective of this study was to elucidate stereoselective mechanisms of propranolol metabolism in man. Five normal subjects were given single 80 mg oral doses of deuterium-labeled pseudoracemates of propranolol, and the stereochemical composition of propranolol and its major metabolites in urine was determined by GC/MS. The (-)/(+)-enantiomer ratios for unchanged propranolol, 1.50 +/- 0.10 (mean +/- s.e. mean), and propranolol glucuronide, 1.76 +/- 0.10, were similar to previous findings in plasma. All products of side-chain oxidation also consisted mainly of the (-)-enantiomer, with an overall (-)/(+) ratio of 1.61 +/- 0.11. A (-)/(+) ratio of 1.04 +/- 0.17 for 4-hydroxypropranolol did not indicate stereoselectivity in ring oxidation. However, the ratio for its glucuronic acid conjugate of 1.78 +/- 0.19 and for its sulphate conjugate of 0.27 +/- 0.03 suggested stereoselectivity in either the glucuronidation or sulphation of 4-hydroxypropranolol, or both. When the stereoselectivity in these secondary pathways was taken into consideration, the overall ring oxidation strongly favoured (+)-propranolol with a (-)/(+)-enantiomer ratio of 0.59 +/- 0.09. The composite observations of the stereochemistry of propranolol metabolism in man are consistent with stereoselective ring oxidation of (+)-propranolol, leading to a greater bioavailability of the pharmacologically more active (-)-propranolol and subsequent preferential side-chain oxidation and glucuronidation of this enantiomer.     

Stereoselective disposition of proton pump inhibitors

It is estimated that about half of all therapeutic agents are chiral, but most of these drugs are administered in the form of the racemic mixture, i.e. a 50/50 mixture of its enantiomers. However, chirality is one of the main features of biology, and many of the processes essential for life are stereoselective, implying that two enantiomers may work differently from each other in a physiological environment. Thus, receptors or metabolizing enzymes would recognize one of the ligand enantiomers in favour of the other. With one exception, all presently marketed proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole and rabeprazole--used for the treatment of gastric acid-related diseases are racemic mixtures. The exception is esomeprazole, the S-enantiomer of omeprazole, which is the only PPI developed as a single enantiomer drug. The development of esomeprazole (an alkaline salt thereof, e.g. magnesium or sodium) was based on unique metabolic properties that clearly differentiated esomeprazole from omeprazole, the racemate. At comparable doses, these properties led to several clinical advantages, for example higher bioavailability in the majority of patients, i.e. the extensive metabolizers (EMs; 97% in Caucasian and 80-85% in Asian populations), lower exposure in poor metabolizers (PMs; 3% in Caucasian and 15-20% in Asian populations) and lower interindividual variation. For the other, i.e. racemic, PPIs there are some data available on the characteristics of the individual enantiomers, and we have therefore undertaken to analyse the current literature with the purpose of evaluating the potential benefits of developing single enantiomer drugs from lansoprazole, pantoprazole and rabeprazole. For lansoprazole, the plasma concentrations of the S-enantiomer are lower than those of the R-enantiomer in both EMs and PMs, and, consequently, the variability in the population or between EMs and PMs is not likely to decrease with either of the lansoprazole enantiomers. Furthermore, plasma protein binding differs between the two lansoprazole enantiomers, in that the amount of the free S-enantiomer is two-fold higher than that of the R-enantiomer. This will counteract the difference seen in total plasma concentrations of the enantiomers. Also, studies using expressed human cytochrome P450 isoenzymes show that the metabolism of one enantiomer is significantly affected by the presence of the other, which is likely to result in different pharmacokinetics when administering a single enantiomer. For pantoprazole, there is a negligible difference in plasma concentrations between the two enantiomers in EMs, while the difference is substantial in PMs. The difference in AUC between PMs and EMs would decrease to some extent, but in the majority of the population the variability and efficacy would not be altered with a single enantiomer of pantoprazole. The metabolism of the enantiomers of rabeprazole displays stereoselectivity comparable to that of lansoprazole, i.e. the exposure of the R-enantiomer is higher than that of the S-enantiomer in EMs as well as in PMs, which, by analogy to lansoprazole, makes them less suitable for development of a single enantiomer drug. Furthermore, the chiral stability of the rabeprazole enantiomers may be an issue because of significant degradation of rabeprazole to its sulfide analogue, which is subject to non-stereoselective metabolic regeneration of a mixture of the two enantiomers. In conclusion, in contrast to esomeprazole, the S-enantiomer of omeprazole, minimal if any clinical advantages would be expected in developing any of the enantiomers of lansoprazole, pantoprazole, or rabeprazole as compared with their racemates.